This application is the second revision of the second competitive renewal of a P01 whose goal was to develop and evaluate approaches for gene therapy in the treatment of localized malignancies, using malignant mesothelioma (MM) as the paradigm. The original P01 evaluated the use of a suicide gene (HSVtk) delivered by an adenoviral (Ad) vector. 34 patients were treated with minimal toxicity and clear cut evidence of superficial gene transfer. There were two long-term survivors whose responses appear to have been due to anti-tumor immune reactions. This led to a redirection of the project to immuno-gene therapy of thoracic malignancies using an adenovirus (Ad) expressing the cytokine Interferon-beta. A Phase 1 trial of intrapleural Ad.lFNbeta for patients with MM and malignant pleural effusions was completed: evidence of anti-tumor immune responses and clinical responses were observed. This new proposal is a highly interlinked group of three projects and three cores. Each component has the same overall goal: to develop effective clinical approaches using immuno- and/or immuno-gene therapy for the treatment of thoracic malignancies. The unifying scientific theme of the P01 is that effective immunotherapy will require interventions at multiple points in the generation of an anti-tumor response. This Project will continue and extend the ongoing clinical trials using Ad.lFNbeta aimed at patients with mesothelioma. This will include a small Phase 1 trial using multiple dosing and Phase 2 trials combining immunotherapy, chemotherapy, and surgery. The second Project will continue to conduct preclinical studies to support the clinical trials. Aims will focus on approaches to augment immunotherapy using inhibitors of immunosuppression, chemotherapy, and vascular disrupting agents. The third Project will develop adoptive immunotherapy for mesothelioma using genetically modified lymphocytes engineered to target the tumor antigen Mesothelin. Core A will continue to supply administrative support. The existing Pathology and Translational Service Cores will be merged into a new Core B entitled the "Tissue Acquisition, Sample Processing, and Pathology Core". Core C will continue to provide biostatistical and data management services. All projects will also make use of a newly established Penn Cancer Center Human Immunology Core for immune analyses. This project should provide new treatment options for patients with malignant mesothelioma who have few current therapeutic options.